Elevated NCOR1 disrupts a network of dietary-sensing nuclear receptors in bladder cancer cells

Increasingly invasive bladder cancer cells lines displayed insensitivity toward a panel of dietary-derived ligands for members of the nuclear receptor superfamily. Insensitivity was defined through altered gene regulatory actions and cell proliferation and reflected both reduced receptor expression and elevated nuclear receptor corepressor 1 (NCOR1) expression. Stable overexpression of NCOR1 in sensitive cells (RT4) resulted in a panel of clones that recapitulated the resistant phenotype in terms of gene regulatory actions and proliferative responses toward ligand. Similarly, silencing RNA approaches to NCOR1 in resistant cells (EJ28) enhanced ligand gene regulatory and proliferation responses, including those mediated by peroxisome proliferator-activated receptor (PPAR) gamma and vitamin D receptor (VDR) receptors. Elevated NCOR1 levels generate an epigenetic lesion to target in resistant cells using the histone deacetylase inhibitor vorinostat, in combination with nuclear receptor ligands. Such treatments revealed strong-additive interactions toward the PPARgamma, VDR and Farnesoid X-activated receptors. Genome-wide microarray and microfluidic quantitative real-time, reverse transcription-polymerase chain reaction approaches, following the targeting of NCOR1 activity and expression, revealed the selective capacity of this corepressor to govern common transcriptional events of underlying networks. Combined these findings suggest that NCOR1 is a selective regulator of nuclear receptors, notably PPARgamma and VDR, and contributes to their loss of sensitivity. Combinations of epigenetic therapies that target NCOR1 may prove effective, even when receptor expression is reduced.

Serum vitamin D levels are lower in Australian children and adolescents with type 1 diabetes than in children without diabetes

Vitamin D is synthesised in the skin through the action of UVB radiation (sunlight), and 25-hydroxy vitamin D (25OHD) measured in serum as a marker of vitamin D status. Several studies, mostly conducted in high latitudes, have shown an association between type 1 diabetes mellitus (T1DM) and low serum 25OHD. We conducted a case-control study to determine whether, in a sub-tropical environment with abundant sunlight (latitude 27.5°S), children with T1DM have lower serum vitamin D than children without diabetes. Fifty-six children with T1DM (14 newly diagnosed) and 46 unrelated control children participated in the study. Serum 25OHD, 1,25-dihydroxy vitamin D (1,25(OH)2D) and selected biochemical indices were measured. Vitamin D receptor (VDR) polymorphisms Taq1, Fok1, and Apa1 were genotyped. Fitzpatrick skin classification, self-reported daily hours of outdoor exposure, and mean UV index over the 35d prior to blood collection were recorded. Serum 25OHD was lower in children with T1DM (n=56) than in controls (n=46) [mean (95%CI)=78.7 (71.8-85.6) nmol/L vs. 91.4 (83.5-98.7) nmol/L, p=0.02]. T1DM children had lower self-reported outdoor exposure and mean UV exposure, but no significant difference in distribution of VDR polymorphisms. 25OHD remained lower in children with T1DM after covariate adjustment. Children newly diagnosed with T1DM had lower 1,25(OH)2D [median (IQR)=89 (68-122) pmol/L] than controls [121 (108-159) pmol/L, p=0.03], or children with established diabetes [137 (113-153) pmol/L, p=0.01]. Children with T1DM have lower 25OHD than controls, even in an environment of abundant sunlight. Whether low vitamin D is a risk factor or consequence of T1DM is unknown. © 2012 John Wiley & Sons A/S.

Genetic control of bone density and turnover: Role of the collagen 1α1, estrogen receptor, and vitamin D receptor genes

Genetic factors are known to influence both the peak bone mass and probably the rate of change in bone density. A range of regulatory and structural genes has been proposed to be involved including collagen 1α1 (COL1A1), the estrogen receptor (ER), and the vitamin D receptor (VDR), but the actual genes involved are uncertain. We therefore studied the role of the COL1A1 and VDR loci in control of bone density by linkage in 45 dizygotic twin pairs and 29 nuclear families comprising 120 individuals. The influences on bone density of polymorphisms of COL1A1, VDR, and ER were studied by association both cross-sectionally and longitudinally in 193 elderly postmenopausal women (average age, 69 years) over a mean follow-up time of 6.3 years. Weak linkage of the COL1A1 locus with bone density was observed in both twins and families (p = 0.02 in both data sets), confirming previous observations of linkage of this locus with bone density. Association between the MscI polymorphism of COL1A1 and rate of lumbar spine bone loss was observed with significant gene-environment interaction related to dietary calcium intake (p = 0.0006). In the lowest tertile of dietary calcium intake, carriers of "s" alleles lost more bone than "SS" homozygotes (p = 0.01), whereas the opposite was observed in the highest dietary calcium intake (p = 0.003). Association also was observed between rate of bone loss at both the femoral neck and the lumbar spine and the TaqI VDR polymorphism (p = 0.03). This association was strongest in those in the lowest tertile of calcium intake, also suggesting the presence of gene-environment interaction involving dietary calcium and VDR, influencing bone turnover. No significant association was observed between the PvuII ER polymorphism alone or in combination with VDR or COL1A1 genotypes, with either bone density or its rate of change. These data support the involvement of COL1A1 in determination of bone density and the interaction of both COL1A1 and VDR with calcium intake in regulation of change of bone density over time.

Vitamin D analogs differentially control antimicrobial peptide/"alarmin" expression in psoriasis

Antimicrobial peptides (AMPs) are strongly expressed in lesional skin in psoriasis and play an important role as proinflammatory "alarmins" in this chronic skin disease. Vitamin D analogs like calcipotriol have antipsoriatic effects and might mediate this effect by changing AMP expression. In this study, keratinocytes in lesional psoriatic plaques showed decreased expression of the AMPs beta-defensin (HBD) 2 and HBD3 after topical treatment with calcipotriol. At the same time, calcipotriol normalized the proinflammatory cytokine milieu and decreased interleukin (IL)-17A, IL-17F and IL-8 transcript abundance in lesional psoriatic skin. In contrast, cathelicidin antimicrobial peptide expression was increased by calcipotriol while psoriasin expression remained unchanged. In cultured human epidermal keratinocytes the effect of different vitamin D analogs on the expression of AMPs was further analyzed. All vitamin D analogs tested blocked IL-17A induced HBD2 expression by increasing IkappaB-alpha protein and inhibition of NF-kappaB signaling. At the same time vitamin D analogs induced cathelicidin through activation of the vitamin D receptor and MEK/ERK signaling. These studies suggest that vitamin D analogs differentially alter AMP expression in lesional psoriatic skin and cultured keratinocytes. Balancing AMP "alarmin" expression might be a novel goal in treatment of chronic inflammatory skin diseases.

Diretrizes para prevenção e tratamento da osteoporose induzida por glicocorticoide

Os glicocorticoides (GC) são prescritos por praticamente todas as especialidades médicas, e cerca de 0,5% da população geral do Reino Unido utiliza esses medicamentos. Com o aumento da sobrevida dos pacientes com doenças reumatológicas, a morbidade secundária ao uso dessa medicação representa um aspecto importante que deve ser considerado no manejo de nossos pacientes. As incidências de fraturas vertebrais e não vertebrais são elevadas, variando de 30%-50% em pessoas que usam GC por mais de três meses. Assim, a osteoporose e as fraturas por fragilidade devem ser prevenidas e tratadas em todos os pacientes que iniciarão ou que já estejam em uso desses esteroides. Diversas recomendações elaboradas por várias sociedades internacionais têm sido descritas na literatura, porém não há consenso entre elas. Recentemente, o Americam College of Rheumatology publicou novas recomendações, porém elas são fundamentadas na FRAX (WHO Fracture Risk Assessment Tool) para analisar o risco de cada indivíduo e, dessa maneira, não podem ser completamente utilizadas pela população brasileira. Dessa forma, a Comissão de Osteoporose e Doenças Osteometabólicas da Sociedade Brasileira de Reumatologia, em conjunto com a Associação Médica Brasileira e a Associação Brasileira de Medicina Física e Reabilitação, implementou as diretrizes brasileiras de osteoporose induzida por glicocorticoide (OPIG), baseando-se na melhor evidência científica disponível e/ou experiência de experts. DESCRIÇÃO DO MÉTODO DE COLETA DE EVIDÊNCIA: A revisão bibliográfica de artigos científicos desta diretriz foi realizada na base de dados MEDLINE. A busca de evidência partiu de cenários clínicos reais, e utilizou as seguintes palavras-chave (MeSH terms): Osteoporosis, Osteoporosis/chemically induced*= (Glucocorticoids= Adrenal Cortex Hormones, Steroids), Glucocorticoids, Glucocorticoids/administration and dosage, Glucocorticoids/therapeutic use, Glucocorticoids/adverse effects, Prednisone/adverse effects, Dose-Response Relationship, Drug, Bone Density/drug effects, Bone Density Conservation Agents/pharmacological action, Osteoporosis/ prevention&control, Calcium, Vitamin D, Vitamin D deficiency, Calcitriol, Receptors, Calcitriol; 1-hydroxycholecalciferol, Hydroxycholecalciferols, 25-Hydroxyvitamin D3 1-alpha-hydroxylase OR Steroid Hydroxylases, Prevention and Control, Spinal fractures/prevention & control, Fractures, Spontaneous, Lumbar Vertebrae/injuries, Lifestyle, Alcohol Drinking, Smoking OR tobacco use disorder, Movement, Resistance Training, Exercise Therapy, Bone density OR Bone and Bones, Dual-Energy X-Ray Absorptiometry OR Absorptiometry Photon OR DXA, Densitometry, Radiography, (Diphosphonates Alendronate OR Risedronate Pamidronate OR propanolamines OR Ibandronate OR Zoledronic acid, Teriparatide OR PTH 1-34, Men AND premenopause, pregnancy, pregnancy outcome maternal, fetus, lactation, breast-feeding, teratogens, Children (6-12 anos), adolescence (13-18 anos). GRAU DE RECOMENDAÇÃO E FORÇA DE EVIDÊNCIA: A) Estudos experimentais e observacionais de melhor consistência; B) Estudos experimentais e observacionais de menor consistência; C) Relatos de casos (estudos não controlados); D) Opinião desprovida de avaliação crítica, com base em consensos, estudos fisiológicos ou modelos animais. OBJETIVO: Estabelecer as diretrizes para a prevenção e o tratamento da OPIG.

Role of low affinity beta1-adrenergic receptors in normal and diseased hearts

ROLE OF LOW AFFINITY β1-ADRENERGIC RECEPTOR IN NORMAL AND DISEASED HEARTS Background: The β1-adrenergic receptor (AR) has at least two binding sites, 1HAR and 1LAR (high and low affinity site of the 1AR respectively) which cause cardiostimulation. Some β-blockers, for example (-)-pindolol and (-)-CGP 12177 can activate β1LAR at higher concentrations than those required to block β1HAR. While β1HAR can be blocked by all clinically used β-blockers, β1LAR is relatively resistant to blockade. Thus, chronic β1LAR activation may occur in the setting of β-blocker therapy, thereby mediating persistent βAR signaling. Thus, it is important to determine the potential significance of β1LAR in vivo, particularly in disease settings. Method and result: C57Bl/6 male mice were used. Chronic (4 weeks) β1LAR activation was achieved by treatment with (-)-CGP12177 via osmotic minipump. Cardiac function was assessed by echocardiography and catheterization. (-)-CGP12177 treatment in healthy mice increased heart rate and left ventricular (LV) contractility without detectable LV remodelling or hypertrophy. In mice subjected to an 8-week period of aorta banding, (-)-CGP12177 treatment given during 4-8 weeks led to a positive inotropic effect. (-)-CGP12177 treatment exacerbated LV remodelling indicated by a worsening of LV hypertrophy by ??% (estimated by weight, wall thickness, cardiomyocyte size) and interstitial/perivascular fibrosis (by histology). Importantly, (-)-CGP12177 treatment to aorta banded mice exacerbated cardiac expression of hypertrophic, fibrogenic and inflammatory genes (all p<0.05 vs. non-treated control with aorta banding).. Conclusion: β1LAR activation provides functional support to the heart, in both normal and diseased (pressure overload) settings. Sustained β1LAR activation in the diseased heart exacerbates LV remodelling and therefore may promote disease progression from compensatory hypertrophy to heart failure. Word count: 270

Ghrelin axis genes, peptides and receptors : recent findings and future challenges

The ghrelin axis consists of the gene products of the ghrelin gene (GHRL), and their receptors, including the classical ghrelin receptor GHSR. While it is well-known that the ghrelin gene encodes the 28 amino acid ghrelin peptide hormone, it is now also clear that the locus encodes a range of other bioactive molecules, including novel peptides and non-coding RNAs. For many of these molecules, the physiological functions and cognate receptor(s) remain to be determined. Emerging research techniques, including proteogenomics, are likely to reveal further ghrelin axis-derived molecules. Studies of the role of ghrelin axis genes, peptides and receptors, therefore, promises to be a fruitful area of basic and clinical research in years to come.

Neuronal nicotinic acetylcholine receptors as pharmacotherapeutic targets for the treatment of alcohol use disorders

Alcohol use disorders (AUDs) are complex and developing effective treatments will require the combination of novel medications and cognitive behavioral therapy approaches. Epidemiological studies have shown there is a high correlation between alcohol consumption and tobacco use, and the prevalence of smoking in alcoholics is as high as 80% compared to about 30% for the general population. Both preclinical and clinical data provide evidence that nicotine administration increases alcohol intake and nonspecific nicotinic receptor antagonists reduce alcohol-mediated behaviors. As nicotine interacts specifically with the neuronal nicotinic acetylcholine receptor (nAChR) system, this suggests that nAChRs play an important role in the behavioral effects of alcohol. In this review, we discuss the importance of nAChRs for the treatment of AUDs and argue that the use of FDA approved nAChR ligands, such as varenicline and mecamylamine, approved as smoking cessation aids may prove to be valuable treatments for AUDs. We also address the importance of combining effective medications with behavioral therapy for the treatment of alcohol dependent individuals.

Dopamine responsiveness is regulated by targeted sorting of D2 receptors

Abstract Aberrant dopaminergic signaling is a critical determinant in multiple psychiatric disorders, and in many disease states, dopamine receptor number is altered. Here we identify a molecular mechanism that selectively targets D2 receptors for degradation after their activation by dopamine. The degradative fate of D2 receptors is determined by an interaction with G protein coupled receptor-associated sorting protein (GASP). As a consequence of this GASP interaction, D2 responses in rat brain fail to resensitize after agonist treatment. Disruption of the D2-GASP interaction facilitates recovery of D2 responses, suggesting that modulation of the D2-GASP interaction is important for the functional down-regulation of D2 receptors.